Opioid use and subsequent delirium risk in patients with advanced cancer in palliative care: a multicenter registry study

The prevalent use of opioids for pain management in patients with advanced cancer underscores the need for research on their neuropsychiatric impacts, particularly delirium. Therefore, we aimed to investigate the potential association between opioid use and the risk of delirium in patients with advanced cancer admitted to the acute palliative care unit. We conducted a retrospective observational study utilizing a multicenter, patient-based registry cohort by collecting the data from January 1, 2019, to December 31, 2020, in South Korea. All data regarding exposures, outcomes, and covariates were obtained through retrospective chart reviews by a team of specialized medical professionals with expertise in oncology. Full unmatched and 1:1 propensity-score matched cohorts were formed, and stratification analysis was conducted. The primary outcome, delirium, was defined and diagnosed by the DSM-IV. Of the 2,066 patients with advanced cancer, we identified 42.8% (mean [SD] age, 64.4 [13.3] years; 60.8% male) non-opioid users and 57.2% (62.8 [12.5] years; 55.9% male) opioid users, respectively. Opioid use was significantly associated with an increased occurrence of delirium in patients with advanced cancer (OR, 2.02 [95% CI 1.22–3.35]). The risk of delirium in patients with advanced cancer showed increasing trends in a dose-dependent manner. High-dose opioid users showed an increased risk of delirium in patients with advanced cancer compared to non-opioid users (low-dose user: OR, 2.21 [95% CI 1.27–3.84]; high-dose user: OR, 5.75 [95% CI 2.81–11.77]; ratio of OR, 2.60 [95% CI 1.05–6.44]). Patients with old age, male sex, absence of chemotherapy during hospitalization, and non-obese status were more susceptible to increased risk of delirium in patients with cancer. In this multicenter patient-based registry cohort study, we found a significant, dose-dependent association between opioid use and increased risk of delirium in patients with advanced cancer. We also identified specific patient groups more susceptible to delirium. These findings highlight the importance of opioid prescription in these patients with advanced cancer, balancing effective doses for pain management and adverse dose-inducing delirium.


Study design and population
This study incorporated 2152 patients with advanced cancer admitted to the ACPU of four centers from January 1, 2019, to December 31, 2020, with follow-up until the date of death or March 31, 2022, based on the admission date.Exclusions were made based on: (1) hospital stay exceeding three months (excluded, n = 5); (2) transfers to other departments (excluded, n = 6); (3) observation of terminal delirium (excluded, n = 3); (4) patient with a history of delirium (excluded, n = 55); and (5) missing baseline characteristics of study subjects (excluded, n = 17).If delirium occurs within two weeks before death, we define it as terminal delirium.Following these criteria, 2066 individuals were included in the analysis.The assessment of opioid use, delirium, and other covariates was conducted through meticulous retrospective chart reviews, ensuring a thorough evaluation of patient histories and clinical outcomes.

Exposure
Opioid exposure was considered for patients who received opioid medications during hospitalization.The morphine equivalent daily dose (MEDD) was used to assess exposed dose levels.We used a cutoff of the upper 25% of the MEDD (100 mg MEDD) threshold to categorize low-dose and high-dose users.Prescriptions of medications were conducted through medical specialists.

Outcome
The primary outcome, delirium in patients with advanced cancer, was identified via medical records and diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 18 .At least two medical specialists performed a detailed review and recorded potentially related symptoms and associated medications.In cases of conflicting opinions, additional experts participated in the diagnosis and voted to reach a conclusion 9 .

Statistical analysis
In this study, we aimed to investigate the association between opioid use and the development of delirium in patients with advanced cancer.To control for potential confounding variables and balance demographic characteristics between comparison groups, we constructed a propensity score (PS)-matching cohort (Fig. 1) 21,[25][26][27] .All variables listed in Table 1 were used for matching, with PS calculated through a multivariate logistic regression model.Individuals with PS differences within the specified caliper (0.1) were matched in a 1:1 ratio using the greedy nearest-neighbor algorithm.Finally, 776 patients were allocated to each of the opioid-exposed and unexposed groups.The adequacy of PS matching was evaluated by standardized mean differences (SMD), with an SMD less than 0.1 indicating no significant imbalance 25 .
Odds ratio (OR) with 95% confidence intervals (CIs) using binary logistic regression models were used for estimation 27 .In addition, an adjusted model was used to minimize the impact of potential confounders, incorporating the following variables: age, sex, chemotherapy during hospitalization, living with family, medical aid recipients, alcohol consumption, smoking, and obesity.Statistical significance was established at a two-sided P value < 0.05.All analyses and visualization were performed using SAS software (version 9.4; SAS Institute Inc., Cary, NC, USA) and R software (version 4.1.0;R Foundation for Statistical Computing, Vienna, Austria) 28,29  ).We conducted this study using deidentified administrative data that were obtained without prior consent.

Findings and explanation
We investigated the impact of opioid use on the occurrence of delirium in patients with advanced cancer admitted to APCU.There are several key findings.First, in this large-scale multicenter patient-based registry cohort study that included 2124 eligible patients, opioid use was significantly associated with an increased occurrence of delirium in patients with advanced cancer.Second, the risk of delirium showed a dose-dependent relationship with opioid dose.High-dose opioid users showed higher odds of delirium in patients with advanced cancer.Third, patients with old age, male sex, absence of chemotherapy during hospitalization, and non-obese status showed a significant risk of delirium in stratification analysis.

Comparison with other studies
Previous studies explored the association between opioid use and delirium in individuals with various surgeries and diseases, including hip fractures, neurological injury, pain, infection, fever, and hypotension 4,10,11,30 ; however, investigations focusing on delirium in patients with advanced cancer are limited.A few studies suggested an association between opioid use and the occurrence of delirium in patients with cancer.However, these studies were limited to case-report studies or small cohort sizes to generalize the results (Table S1) [6][7][8]31 . By ontrast, our large-scale multicenter patient-based registry cohort, including 2124 eligible patients admitted to the APCU, highlighted the significant association between opioid use and delirium in patients with advanced cancer.

Possible mechanisms
Opioids are known to exert their effects primarily through the central nervous system by altering neurotransmitter release and neuronal activity 32 .This alternation can lead to neuropsychiatric outcomes, including cognitive impairment and delirium, particularly in patients with advanced cancer 3,4 .Moreover, opioids can disrupt the normal sleep-wake cycle, further exacerbating the risk of delirium 33 .In this cohort study, we found that the association between opioid use and the occurrence of delirium followed a dose-dependent nature.Higher doses of opioids are more likely to induce significant changes in the brain circuits by altering synaptic functions and neural pathways 34 , potentially leading to a higher risk of delirium.
The patients with old age, male sex, absence of chemotherapy during hospitalization, and underweight status showed a significant risk of delirium in stratification analysis.These factors were aligned with identified risk factors for delirium in patients with cancer 9 .Older patients often have decreased physiological reserve and increased sensitivity to opioids, which can predispose them to delirium 35 .Moreover, the significant risk of delirium among male patients could be attributed to a higher incidence of hyperactive forms of delirium in males compared to females 9 .This discrepancy may also suggest potential underdiagnoses of delirium in female patients.
Furthermore, underweight individuals may exhibit different pharmacokinetics and pharmacodynamics, making them more susceptible to delirium 36 .This phenomenon aligns with the concept known as the "Obesity Paradox," where individuals with a higher body mass index (BMI) appear to possess protective factors against postoperative delirium 9,36 .This paradoxical relationship suggests that, similarly, in cancer patients, those with a higher BMI might exhibit a lower risk of delirium, highlighting the complex interplay between body weight and neuropsychiatric outcomes in medical conditions.The absence of chemotherapy during hospitalization could be indicative of a more advanced stage of cancer, where the physiological and psychological burden of the disease itself, coupled with opioid use, could heighten the risk of delirium.

Policy implications
Our findings not only highlight the need for cautious opioid use in patients with advanced cancer but also emphasize the broader impact of delirium 37 .Delirium poses a significant burden, not only affecting the patients but also placing a significant social burden on their families and healthcare providers 9 .In the context of advanced cancer, delirium adversely impacts the disease course by impairing communication and hindering the participation of patients in care, such as treatment decisions, counseling, and diagnosis 5 .Therefore, policy implications should extend beyond clinical management to include supportive measures for families and caregivers.Healthcare systems should implement policies promoting regular mental status assessments, individualized pain management strategies, and comprehensive support systems for patients with advanced cancer.These measures should be designed to minimize the occurrence of delirium and its associated burdens, thereby improving the overall conditions of patients and families in advanced cancer care contexts.

Strengths and limitations of the study
This study presents a novel association between opioid use and delirium among patients with advanced cancer by utilizing data from a large-scale, multicenter, patient-based registry cohort.However, several limitations must be acknowledged.First, we collected the information on opioid use relying on the medical records, but they do not necessarily equate to actual consumption of the medication, leading to potential exposure misclassification.Second, while we observed an association, the observational nature of our study precludes a definitive explanation of the causal relationship.It remains unclear whether the association is due to the chronic pain associated with cancer or the opioids themselves.This ambiguity underscores the need for future research to determine the appropriate dosage of opioids that balances analgesic effects and the risk of delirium, as well as to explore the underlying mechanisms.Third, our focus on patients with advanced cancer admitted to the APCU limits the generalizability of our findings to the general patients with cancer.Further studies are needed to assess whether these associations are consistent in patients with less advanced stages of cancer and in different care settings.Fourth, our study is subject to the inherent limitations of a retrospective observational design 38 .The reliance on a patient registry and retrospective chart reviews for evaluating exposures, outcomes, and covariates may introduce bias and affect the generalizability of our findings.To mitigate these limitations, we employed PS matching; however, we acknowledge that it does not fully address the problem 38 .Fifth, the prevalence of delirium observed in our study is lower than in previous studies.However, it is important to note that patients with advanced cancers often exhibit hypoactive delirium, which is more challenging to detect due to its less pronounced symptoms 39 .Thus, the nature of our retrospective chart review study may have resulted in the under-diagnosis of hypoactive delirium.

Conclusion
In this multicenter patient-based registry cohort study, opioid use was significantly associated with a substantial increase in the risk of delirium in patients with advanced cancer.This association was observed to be dosedependent, with higher opioid dosages associated with an increased risk of delirium.In addition, we identified various vulnerable groups, including old age, male sex, absence of chemotherapy during hospitalization, and underweight status, for delirium among patients with advanced cancer.These findings highlight the critical need for healthcare providers to carefully prescribe opioids to manage pain in patients with advanced cancer; however, further studies are needed to focus on determining the optimal opioid dosages that minimize the risk of delirium and investigating underlying mechanisms of these associations.

Figure 2 .
Figure 2. Dose-dependent association between MEDD and incidence of delirium.Morphine equivalent daily dose.

. Figure 1. Density
plot and box plot of 1:1 propensity score matching cohort.